Spinal Muscular Atrophy as a Treatable Disease: Disease-Modifying Therapies Improving Clinical Outcomes and Quality of Life

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by progressive skeletal muscle hypotonia affecting voluntary movements.1 A recessive mutation in the survival motor neuron 1 (SMN1) gene, which is required for proper production of the SMN protein, leads to irreversible loss of α motor neurons in the ventral spinal cord and motor nuclei in the lower brainstem. Symmetric, proximal greater than distal, and progressive muscle weakness is the hallmark symptom.
SMA is the second most common autosomal recessive disorder worldwide and the most common cause of infant mortality, with an estimated incidence of 1 in 10,000 live births and estimated prevalence of 1 to 2 per 100,000 persons (Figure 1).3 Approximately 2% of SMA cases are de novo mutations.2  

The pathogenesis of SMA centers around a mutation in the SMN1 gene that causes the absence of exon 7, which encodes 90% of the genetic material for the SMN protein. The other 10% of genetic material is encoded by the survival motor neuron 2 (SMN2) gene.3 SMN2 and SMN1 share 99% of nucleotide identity, except that SMN2 does not transcribe exon 7.4 However, the SMN2 gene copy number is the most important modifier for SMA disease severity. If an individual has a higher number of SMN2 copies in the absence of SMN1, the prognosis may be better.5 SMA is classified by types 0 to 4 with lower numbers reflecting greater clinical severity (Table 1).1-3

Patients with type 0 typically have 1 SMN2 copy, patients with type 1 have 1 to 2 SMN2 copies, patients with type 2 have 3 SMN2 copies, patients with type 3 have 3 to 4 SMN2 copies, and patients with type 4 have 4 or more SMN2 copies (Figure 2).1,3 Type 1 is the most common type, with approximately 60% of cases worldwide. 3

Multiplex ligation-dependent probe amplification (MLPA) is a convenient, highly sensitive deletion test that can determine the copy numbers of both SMN1 and SMN2. For this reason, it is one of the most popular laboratory tests used for diagnosing SMA.1
There are 2 approaches to treatment once a diagnosis for SMA has been made: SMN2 modulators and SMN1 gene therapy. SMN2 modulators alter SMN2 messenger RNA (mRNA) to transcribe exon 7 and produce a full-length SMN protein, and SMN1 gene therapy delivers the SMN1 gene directly to DNA via a viral vector. Historically, SMA treatment consisted of supportive care only. The arrival of disease-modifying therapies has made a major impact on the prognosis for patients with SMA.
There are currently 3 therapies approved by the US Food and Drug Administration (FDA) for the treatment of SMA, with several others under investigation (Table 2).1-7 Additionally, research is being conducted on the effectiveness of combining the 2 existing types of SMA therapies.1 

SMN2 Modulators

Nusinersen. Nusinersen is an antisense oligonucleotide that modifies pre-mRNA splicing of the SMN2 gene to promote the inclusion of exon 7 in the mRNA resulting in a full-length, functional SMN protein.6
The ENDEAR trial (ClinicalTrials.gov Identifier: NCT02193074) is a phase 3 study that tested the safety of nusinersen in 121 infants with SMA who were randomly assigned in a 2 to 1 ratio to receive nusinersen or placebo over a 10-month period. Investigators found a significantly higher percentage of patients in the nusinersen group (41%) experienced positive motor milestone response compared with patients in the control group (0%). The overall survival rate was significantly higher in the patients in the nusinersen group vs the control group (P =.004).6 Similar positive motor milestone efficacy was seen in CHERISH (ClinicalTrials.gov Identifier: NCT02292537), a phase 3 trial that enrolled 126 children aged 2 to 12 years with experienced symptom onset at 6 months of age and older.7 Children were randomly assigned in a 2 to 1 ratio to received nusinersen or placebo over a 9-month period. Both of these trials were stopped early given their compelling results.6,7
Nusinersen does not cross the blood-brain barrier and is administered intrathecally in 4 doses over 2 months followed by a maintenance dose every 4 months.8 In December 2016, nusinersen became the first FDA-approved pediatric and adult treatment for SMA.9
The most common adverse events linked to nusinersen are upper- and lower-respiratory tract infections, atelectasis, constipation, headache, back pain, and post-lumbar puncture syndrome. Nusinersen has no known drug-drug interactions. Ongoing studies are assessing long-term drug-drug interactions and safety risks since most of the clinical trials investigating nusinersen lasted less than 18 months in duration.10
The steep price, possible non-reimbursement from insurance, and a complicated intrathecal administration, especially in patients with scoliosis, are some of the drawbacks of this drug.10,11
Risdiplam. Risdiplamis a small molecule SMN2 splicing modifier with high specificity for exon 7.12
The safety, efficacy, and tolerability of risdiplam were assessed in the FIREFISH trial (ClinicalTrials.gov Identifier: NCT02913482), a 2-part study that enrolled 21 infants with SMA type 1 and 2 copies of SMN2 aged 1 to 7 months at time of enrollment.13 In part 1 of the trial, 93% of infants showed an increase in their Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score, and 14 infants had an overall increase in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) milestones over the course of 8 months. The Hammersmith Infant Neurological Examination Module 2 milestones include rolling to the side or going from prone to supine, sitting with or without support, horizontal or upward kicking, and full head control. No drug-related adverse events were reported.13 In part 2 of the trial, which included an additional 4 months of treatment, 29% of infants could sit unsupported for at least 5 seconds, which is a major milestone achievement for infants with SMA type 1. After 23 months of treatment, 95% of the surviving infants were able to swallow and 89% were able to orally feed. The trial survival rate was 93% after 12 months of treatment.13
Risdiplam is administered daily as an oral liquid. After receiving FDA-approval in patients aged 2 months and older, risdiplam became the first orally deliverable small molecule therapy for the treatment of SMA.14
The most common adverse events associated with risdiplam were fever, rash, oral ulcers, joint pain, diarrhea, and urinary tract infections. Infants treated with risdiplam also had upper respiratory tract infections, pneumonia, vomiting, and constipation. Pregnancy testing is recommended in women of reproductive age before beginning treatment.12
Risdiplam is suitable for patients with SMA who have tolerability or immune response concerns regarding gene therapy. The treatment is easy to administer and works systemically.10

SMN1 Gene Therapy

Onasemnogene abeparvovec. Onasemnogene abeparvovecis an adeno-associated virus 9 (AAV9) vector that delivers wild-type SMN1 to motor neurons, muscle, and other peripheral tissues where SMN1 is expressed.8
In a 2019 study, 12 infants with SMA type 1 who received a one-time dose of onasemnogene abeparvovec had a survival rate of 100% at 24 months compared with a rate of 38% in a historical cohort.15 The infants who were treated with onasemnogene abeparvovec also had improved Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores compared with a historical cohort whose scores decreased by 24 months of age. The infants who received onasemnogene abeparvovec achieved several motor milestones, including sitting unassisted and walking.15
Onasemnogene abeparvovec needs to be monitored closely for safety and tolerability. High doses of AAV vectors expressing human SMN may cause acute hepatotoxicity and sensory neuron toxicity.8
Onasemnogene abeparvovec can cross the blood-brain barrier and only requires a one-time injection to produce a sustained systemic expression of SMN protein.8 It was approved by the FDA for the treatment of SMA in patients aged 2 years and younger.16
A potential issue with the effectiveness of onasemnogene abeparvovec is the presence of anti-AAV9 antibodies in patients with SMA.17 Individuals who become naturally infected with AAVs can mount adaptive immune responses driven partly by innate immune responses to a helper virus such as adenovirus.18 The neutralizing antibodies could block gene transfer to cellular targets. However, humans typically have low titers of AAV9.17

What is the greatest determinant of SMA severity?
The SMN2 gene copy number.

Newborn Screening

One of the ways to maximize normal functioning in infants with SMA before the irreversible loss of motor neurons is to start treatment in the pre-symptomatic period. A newborn screening can identify such infants.19 Treatment before symptoms surface leads to the greatest benefits for survival prognosis, motor development, and reduced need for permanent ventilation.20 Newborn screening is especially helpful for patients with SMA type 1 because rapid motor unit loss can occur within the first 3 months of life and more than 95% of motor units are lost within 6 months of life.1
An Australian study screened dried blood spots of 103,903 newborns using polymerase chain reaction to diagnose infants with SMA.20 Investigators followed up with the infants for several months. One infant who started nusinersen therapy while symptomatic on day 33 of life had a normal neurological exam aside from mild head-lag on pull to sit when the infant was 5 months of age. Another infant who started nusinersen therapy while symptomatic on day 21 of life had restored truncal tone and improved functional motor scores at 4 months of age. Both infants remain free of permanent ventilation and are fully orally fed.20
The NURTURE trial (ClinicalTrials.gov Identifier: NCT02386553), a phase 2, open-label, single-arm, multinational study, examined clinical outcomes in 25 infants with SMA who underwent a 5-year treatment period with nusinersen before SMA symptoms were present. The interim analysis reported no infant deaths or permanent respiratory ventilation requirements after approximately 4 years of treatment and 100% of infants achieved the ability to sit without support. Of these patients, 84% reached the milestone set by the World Health Organization’s timeframe for healthy children. There were 4 infants who needed respiratory support for extended periods of time.21

Lifestyle Modifications

Metabolic dysfunction, such as hyperlipidemia and glucose intolerance, has been reported in SMA mouse models and patient groups.22 Lifestyle modifications may benefit the clinical severity of patients with SMA. A study published in 2019 assessed the effect of 10 months of low-intensity running and high-intensity swimming on mice with mild SMA-like characteristics. Investigators found that both exercises improved the mice’s lipid metabolism and glucose homeostasis. They recommended long-term physical exercise as a “therapeutic intervention for [patients with SMA], in complement to pharmacological or gene-therapies.”23 

Managing Multiorgan System Effects

The absence of SMN protein can affect multiple organ systems, including the heart, kidney, liver, pancreas, spleen, and immune system (Table 3). 2 This can manifest as congenital heart defects, cardiac rhythm abnormalities, sleep disturbances, impaired kidney function, and pancreatic defects.2 As patients live longer due to the advent of new therapies, multisystem comorbidities become more prevalent for this patient population.1 In 2018, the SMA Care Group — a panel of experts including geneticists, orthopedists, pulmonologists, physical therapists, and nutritionists — presented updated and comprehensive guidelines for treating comorbid outgrowths of SMA.24,25 The SMA phenotypic variation, patient preferences, cultural differences, and access to care all factor into decisions about how to best manage comorbidities.19


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                                                                                                                                       Reviewed April 2022